Genetics May Play Role in Colon Cancer, Researchers Find

An underlying genetic susceptibility may be present in the majority of people who develop colorectal cancers and pre-malignant colon polyps, researchers at the University of Utah Medical Center in Salt Lake City reported in today’s New England Journal of Medicine.

The researchers said their study of 670 Utah residents provided strong evidence of an interaction between inherited genes and other factors, such as diet and increasing age, to determine why some people are at greater risk than others of developing the colon abnormalities.

“Inherited susceptibilities play a much more common role than previously thought,” said Dr. Randall W. Burt, an associate professor of medicine at the University of Utah and the senior author of the study. “Our estimate . . . is that a third of the population we studied carries a gene, or genes, which increases their susceptibility to developing colon cancer or colon polyps.”

The results, including the estimate that about one-third of individuals have the genetic susceptibility to colon cancer, “should be applicable to white populations in general,” according to the report.

But the researchers acknowledged that analysis of “a much larger data set” will be necessary to determine if the Utah findings actually apply to other populations.

For example, the University of Utah results are contradicted by a smaller study of Kaiser-Permanente patients in Northern California that was published in the journal Gastroenterology in February.

That study involved examinations of 154 close relatives of people with colon cancer. It found no evidence of a “clear family link” in the development of colon abnormalities, according to Dr. Seymour Grossman, the chief of gastroenterology at the Kaiser-Permanente Medical Center in Oakland and the study’s principal author. Compared to what would be expected in the general population, “we found no increase in either (cancers) or polyps,” Grossman said in a telephone interview.

Despite their apparently conflicting results, both Burt and Grossman said in telephone interviews that the new data underscored the need for close relatives of people with colorectal cancers or polyps to have regular screening tests, such as rectal exams, stool blood tests and sigmoidoscopy, the examination of the colon with a lighted tube.

Such regular screening tests are already recommended by the American Cancer Society and most physicians for all adults starting between ages 40 and 50, but are generally ignored, Burt said. “We are not advising new screening guidelines, but just closer adherence to the already recommended” guidelines, he said.

Specifically, Burt said the new data, as well as Grossman’s earlier results, did not support increased screening for colon cancer with colonoscopy, an examination of the entire colon with a special fiber-optic-lighted tube. The exam requires anesthesia and can cost more than $1,000.

Colorectal cancer is the most common malignancy in both men and women in the United States; an estimated 147,000 new cases will be diagnosed this year, according to the American Cancer Society. As a cause of death, it ranks second to lung cancer in men and third after breast cancer and lung cancer in women.

Most colorectal cancer cases appear to arise from pre-malignant abnormalities, called “adenomatous polyps.” These mushroom-like growths arise in the wall of the intestine and increase in frequency with advancing age.

About three to four times the number of individuals who have been diagnosed with colon cancer are thought to have colon polyps, according to Burt. About 5% of these polyps will develop into cancers if they are not removed, he said. (The larger a polyp, the more likely it is to be malignant.)

The University of Utah study, which expands on an early study that the researchers published in the New England Journal in 1985, involved 670 people from 34 family groupings, called kindreds. The kindreds were selected because either a single person had been diagnosed with a polyp or a cluster of relatives had been diagnosed with colon cancer.

Polyps were found in 19% of the living relatives of those who had been diagnosed with the colon abnormalities, compared with 12% of spouses, who served as controls. The study participants were examined with a flexible sigmoidoscope.

Most Likely Explanations

The researchers then used computers and genetic analysis techniques to determine the most likely explanations for their results. They were aided by extensive genealogies maintained by many of the Mormon families that participated in the study; this allowed large numbers of related individuals to be located.

This statistical analysis led to several conclusions. First, about one-third of the individuals studied appeared to have this genetic susceptibility. Second, not everyone who has the gene will develop a polyp or cancer--only about three in five are likely to develop colon abnormalities by age 80. Finally, they determined that a majority of the colon cancers and polyps, including those in the spouses who served as controls, appeared to be related to this inherited susceptibility.

‘Susceptibility Gene’

“We believe that many if not most colon cancers develop because people have a susceptibility gene and then are exposed to adverse environmental factors,” such as “a low-fiber and high-fat diet,” Burt said. One possibility is that the genetic susceptibility influences the rate of growth of polyps once they develop, he said.

Burt and Lisa Cannon-Albright, the geneticist/statistician who was the principal author of the study, said they did not have sufficient data to draw more specific conclusions, for example, about the exact number of genes involved.

Environmental factors and increasing age “appear to play an important role (in the development of cancer) in individuals who inherit the susceptibility, but they may also play an important role in those who don’t inherit it,” Cannon-Albright said.

Separate Paper

In a separate paper in the New England Journal, researchers from Johns Hopkins Medical Center in Baltimore and other University of Utah researchers described some of the genetic changes that occur during colorectal tumor development. In a journal editorial, Dr. Peter C. Nowell of the University of Pennsylvania School of Medicine said the analysis of such genetic changes was “already proving useful in diagnosis and prognosis; the hope for the future is that they may be useful for designing specific therapy.